What changed in this filing

/stocks — the workspaceLOADING

Item 1. Business

2024-06-24 compared with 2023-07-07 · 291 added, 300 removed, 278 unchanged (68% of the section changed)

IGC Pharma, Inc., formerly known as India Globalization Capital Inc., is a clinical-stage pharmaceutical company with a diversified revenue model that develops both prescription drugs and over-the-counter (OTC) products.

IGC is a Maryland corporation established in 2005 with a fiscal year that is a 52- or 53-week period that ends on March 31.

IGC Pharma, a clinical-stage company developing treatments for Alzheimer’s disease, is committed to transforming patient care by offering faster-acting and more effective solutions.

Our lead drug, IGC-AD1, embodies this vision by tackling a critical challenge – managing agitation in Alzheimer’s dementia.

Early results from our Phase 2 trial are promising:

IGC-AD1 effectively reduced agitation in patients compared to a placebo, and crucially, it did so much faster than traditional medications.

While existing anti-psychotics can take a long 6 to 12 weeks to show effects, IGC-AD1 has the potential to act within two weeks.

This significantly faster onset of action could significantly improve patient care and represents a potential breakthrough in managing Alzheimer’s-related agitation.

IGC Pharma is on a mission to transform Alzheimer’s treatment.

We are building a robust pipeline of five drug candidates, each targeting different aspects of the disease.

Our lead investigational drug tackles agitation, a major burden for patients and caregivers.

By addressing neuroinflammation, it offers a faster-acting solution compared to traditional medications.

Through pre-clinical studies, TGR-63 has demonstrated its potential to disrupt the progression of Alzheimer’s by targeting Aβ plaques, a key disease hallmark.

At the preclinical stage, IGC-1C represents a potential breakthrough by targeting tau protein and neurofibrillary tangles, aiming to modify the disease course.

Also in preclinical development, IGC-M3 focuses on early intervention by inhibiting Aβ plaque formation, potentially slowing cognitive decline.

In preclinical development, LMP is designed to target multiple hallmarks of Alzheimer’s disease, including Aβ plaques and neurofibrillary tangles for a comprehensive therapeutic effect.

We are also harnessing the power of Artificial Intelligence (“AI”) to develop early detection models, optimize clinical trials, and explore new applications for our drugs.

Additionally, our 28 patent filings, including for IGC-AD1, demonstrates our commitment to innovation and protecting our intellectual property.

IGC is a Maryland corporation established in 2005 with a fiscal year ending on March 31, spanning a 52- or 53-week period.

IGC has two business segments:

Life Sciences and Infrastructure.

Our focus is on developing innovative therapies for neurological disorders such as Alzheimer’s disease, epilepsy, Tourette syndrome, and sleep disorders.

We also focus on formulations for eating disorders, chronic pain, premenstrual syndrome (PMS), and dysmenorrhea, in addition to health and wellness OTC formulations.

The Company is developing its lead candidate, IGC-AD1, an investigational oral therapy for the treatment of agitation associated with Alzheimer’s disease.

IGC-AD1 is currently in Phase 2 (Phase 2B) clinical trials after completing nearly a decade of research and realizing positive results from pre-clinical and a Phase 1 trial.

This previous research into IGC-AD1 has demonstrated efficacy in reducing plaques and tangles, which are two important hallmarks of Alzheimer’s, as well as reducing neuropsychiatric symptoms associated with dementia in Alzheimer’s disease, such as agitation.

Alzheimer’s is a progressive neurodegenerative disorder characterized by memory loss, cognitive decline, and behavioral changes.

As the most common cause of dementia, it affects over 50 million people worldwide.

The disease is associated with the accumulation of plaques and tangles in the brain, leading to brain cell deterioration and impaired cognitive functions.

Currently, there is no cure for Alzheimer’s, and the projected cost of Alzheimer’s and associated dementia is expected to be around $1 trillion just in the U.S., placing a significant financial strain on individuals, families, and the healthcare system.

The progress we are making in clinical trials gives us confidence in the potential of IGC-AD1 to be a groundbreaking therapy, with the potential to treat Alzheimer’s and also to manage devastating symptoms that separate families, increase admissions to nursing homes, and drive the cost of Alzheimer’s care.

We have filed forty-one (41) patent applications in different countries and secured nine patents, including control of four in the Alzheimer’s space.

We have built a facility for a potential Phase 3 trial and have strategic relations for the procurement of Active Pharmaceutical Ingredients (APIs).

In addition, we have acquired and initiated work on TGR-63, a pre-clinical molecule that exhibits an impressive affinity for reducing neurotoxicity in Alzheimer’s cell lines.

The advancement of IGC-AD1 into Phase 2 trials represents a significant milestone for the Company and positions us for multiple pathways to future success.

We anticipate that the positive outcomes from these and other trials will drive further growth, valuation, and market potential for IGC-AD1, although there can be no assurance thereof.

At IGC Pharma, we recognize the significance of operational excellence and cost management in clinical trials.

We have established an internal capability to manage trials, including proprietary software, rather than working with an external Contract Research Organization (CRO).

We believe this empowers us to substantially reduce the costs associated with clinical trials compared to relying on external CROs.

Our proprietary software allows us to streamline the trial processes, enabling seamless coordination and data management.

Additionally, we are integrating machine learning technologies into our software framework.

We believe this overlay of Artificial Intelligence (AI) will help us simulate trial scenarios, generate new insights to facilitate improved decision-making, efficiently design our Phase 3 trial, provide advanced data analysis, and ultimately enhancing the effectiveness and efficiency of our clinical trials, although there can be no assurance thereof.

Life Sciences Segment

IGC develops advanced formulations for treating diseases and conditions, including Alzheimer’s disease (AD), menstrual cramps (dysmenorrhea), premenstrual syndrome (PMS), and chronic pain.

The Company’s leading drug candidate, IGC-AD1, has demonstrated in Alzheimer’s cell lines the potential to be effective in suppressing or ameliorating two key hallmarks of Alzheimer’s:

plaques and tangles.

IGC-AD1 is currently in a Phase 2B safety and efficacy clinical trial for agitation in dementia from Alzheimer’s (clinicaltrials.gov, NCT05543681).

The Company also has a line of consumer product such as Holief TM , which includes gummies and pain relief creams for women experiencing PMS and menstrual cramps, all currently available for purchase.

Pharmaceutical :

Since 2014, the Company has focused primarily on the potential uses of phytocannabinoids, including Tetrahydrocannabinol (THC) and Cannabidiol (CBD), in combination with other compounds to treat multiple diseases, including Alzheimer’s.

As a company engaged in the clinical-stage pharmaceutical industry, we focus our research and development efforts, subject to results of future clinical trials, on seeking pharmaceutical solutions that may a) alleviate neuropsychiatric symptoms such as agitation, anxiety, and depression associated with dementia in Alzheimer’s disease;

and b) halt the onset, progression, or cure Alzheimer’s disease.

The Company currently has two main investigational small molecules in various stages of development:

IGC-AD1 , our lead therapeutic candidate, is a THC based formulation that has demonstrated in AD cell lines, in vitro, the potential in reducing a key peptide responsible for Aβ plaques and the potential to decrease or inhibit the phosphorylation of tau, a protein that is responsible for the formation of neurofibrillary tangles, both important hallmarks of AD.

In addition, Phase 1 human trial results demonstrated IGC-AD1’s potential to reduce agitation in dementia due to AD.

IGC-AD1 is currently in Phase 2B trials for treating agitation in dementia from AD, a condition that affects over 10-million individuals in North America and Europe, and

TGR-63 , a non-cannabinoid molecule, is an enzyme inhibitor shown in pre-clinical trials to reduce neurotoxicity in Alzheimer’s cell lines.

Neurotoxicity causes cell dysfunction and death in Alzheimer’s disease.

If shown to be efficacious, in AD cell lines, in halting this process, this inhibitor has the potential to treat Alzheimer’s disease by ameliorating Aβ plaques.

Over-the-Counter Products :

We created a women’s wellness brand, Holief™ available through online channels that is compliant with relevant federal, state, and local laws and regulations.

Holief™ is an all-natural, non-GMO, vegan, line of over-the-counter (OTC) products aimed at treating menstrual cramps (dysmenorrhea) and premenstrual symptoms (PMS).

The products are available through Amazon and other online channels.

Alzheimer ’ s disease

The National Institute on Aging (NIA) at the National Institutes of Health (NIH) defines Alzheimer’s as an irreversible, progressive brain disorder that destroys memory and thinking skills.

According to the Alzheimer’s Association, approximately 11% of Americans over 65 have Alzheimer’s dementia, and many more could be undiagnosed.

Some researchers suspect half of the 80 and over population will develop Alzheimer’s (Alzheimer’s Association, 2023).

Alzheimer’s is the third leading cause of death, after heart disease and cancer.

The Alzheimer’s crisis is growing, and by 2030, World Health Organization (WHO, 2020) estimates that 55 million people worldwide will have dementia.

With no approved cure, the global cost of dementia is expected to rise to about $2.8 trillion by 2030.

Dementia is a broader term used to describe the loss of cognitive functioning, including thinking, remembering, reasoning, and behavioral abilities.

The WHO believes Alzheimer’s may be responsible for up to 70% of dementia.

Alzheimer’s disease, and the dementia associated with it, is a progressive disease.

Symptoms such as agitation, anxiety, depression, sleep disturbance (sundown syndrome), delusions, and hallucinations often begin to appear in patients in their mid-60s.

The NIA categorizes Alzheimer’s in three stages–- mild, moderate, and severe (NIA, 2019).

Symptoms of mild Alzheimer’s can include wandering (getting lost, not remembering the way home), trouble handling money and paying bills, repeating questions, and personality or behavior changes.

As the disease progresses to moderate, there is damage to the areas of the brain that control language, reasoning, sensory processing, and conscious thought.

Patients can have difficulty with multi-step tasks such as getting dressed.

Behavioral problems, including hallucinations, delusions, paranoia, and impulsive behavior, can also increase.

When severe Alzheimer’s sets in, plaques and tangles spread throughout the patient’s brain, and the brain shrinks significantly.

People with severe Alzheimer’s are completely dependent on others for care.

They cannot communicate, and near the end of their life, they may be largely bedridden as the body shuts down (NIA, 2021).

Currently, there are limited options to help Alzheimer’s patients with the debilitating symptoms of the disease or relief for the burden placed on their caregivers (Cheng, 2017).

Our Phase 1 trial for IGC-AD1 may provide hope for those patients suffering from mild to severe dementia due to Alzheimer’s disease.

Alzheimer ’ s Disease (AD) Pathology

Alzheimer’s pathology can be divided into two categories, familial or inherited AD and sporadic AD.

Life Sciences Segment and Infrastructure Segment.

Please refer to Note 1, “Nature of Operations” and Item 8 of this Annual Report on Form 10-K, for further information on business segments .

Our Business Strategy

The business strategy includes:

Subject to FDA approval and clinical trials, developing IGC-AD1 as a drug for treating agitation in dementia due to Alzheimer’s.

Subject to FDA approval, developing IGC-AD1 as a drug for treating Alzheimer’s disease.

Developing TGR-63 for the potential treatment of Alzheimer’s disease.

Driving revenue from in-house OTC brands and formulations.

Core business competencies and advantages

Our core competencies include:

a network of doctors, scientists with Ph.D.

degrees, and intellectual property legal experts with a sophisticated understanding of drug discovery, research, FDA filings, intellectual protection, and product formulation;

knowledge of various cannabinoid strains, their phytocannabinoid profile, extraction methodology, and impact on various pathways;

knowledge of plant and cannabinoid-based combination therapies;

knowledge of research and development in the field;

approximately twenty-eight (28) patent applications out of which our portfolio includes twelve (12) granted patents.

For more information, please refer to Item I, “Business” of Part I;

facilities and a team with experience in manufacturing, marketing, and selling products.

These competencies have enabled us to make progress on our business goals, specifically completing the Phase 1 clinical trial of IGC-AD1, which has the potential to positively impact the lives of millions of patients suffering from the symptoms of Alzheimer’s disease, subject to FDA approval.

Background on Alzheimer ’ s Disease Pathology

Alzheimer’s disease (“AD”) pathology can be divided into two categories:

familial or inherited AD and sporadic AD.

The histopathology of early-onset familial AD and late-onset sporadic AD are indistinguishable.

9 unchanged sentences

The misfolded structure of Aβ proteins, along with NFTs, generates a characteristic tendency for their aggregation (Chiti & Dobson, 2006) around damaged or dead neurons and within cerebral vasculature in the brain.

It manifests by memory loss followed by progressive dementia.

It manifests in memory loss followed by progressive dementia.

It has long been believed that Aβ1–40 (Aβ40) and Aβ1–42 (Aβ42) aggregates are the constituents of the insoluble plaques that are characteristic of AD.

4 unchanged sentences

Pillay, et al., 2004).

The two hallmarks of Alzheimer’s are shown in Figure 1.

Hallmarks of Alzheimer ’ s

7 unchanged sentences

● Neuroinflammation

IGC-AD1 Studies on Alzheimer ’ s

While investigating cannabinoid-based combination therapies, researchers at the University of South Florida (USF) discovered the potential for cannabis to play a role in treating Alzheimer’s.

The discovery was featured on Dr.

Sanjay Gupta’s CNN show Weed 2.

This work also led to several patent filings including one that was granted by the United States Patent and Trademark Office (USPTO).

In fiscal year 2018, IGC acquired exclusive rights to the research data and patent filing.

The research on the active ingredients of IGC-AD1 (IGC-AD1 Actives) showed that they, in combination, had potentially positive effects on Alzheimer’s disease.

Specifically, the pre-clinical research on the IGC-AD1 Actives showed the following:

Impact on plaque levels:

Cao et al., (2014) reported a dose-dependent decrease in Aβ40 levels in N2a/AβPPswe cells (AD cell lines) in the presence of the IGC-AD1 Actives, after 24 hours of incubation.

Furthermore, repeated exposure reduced Aβ40 levels without changing APP levels, a novel non-obvious, and important finding as APP is a key protein associated with brain functioning.

The mode of action is attributed to its direct interaction with Aβ protein and inhibition of Aβ aggregation (Cao et al., 2014).

Impact on Tau Protein :

IGC-AD1 Actives lowered the level of phosphorylated Tau (pTau) expression in N2a/AβPPswe cells in a dose-dependent manner.

The mode of action was attributed to the direct interaction of IGC AD1 Actives with GSK3 protein kinase, which lowers pTau expression (Cao et al., 2014).

Impact on neurotoxicity :

Analysis of the neurotoxicity at various doses in N2a/AβPPswe cells after incubation for up to 24 hours showed that the IGC-AD-1 Actives were non-toxic to cells at all doses (Cao et al., 2014).

Impact on Mitochondria :

In a novel and non-obvious finding, it was discovered that THC in low doses has the unique property of enhancing mitochondrial functioning in isolated mitochondria obtained from N2a/AβPPswe cells (Cao et al., 2014).

This finding is contrary to what THC does at higher doses, alluding to a bi-phasic nature of THC.

Results with a mouse model:

Cao’s group extended their in vivo study to aged APP/PS1 mice to evaluate THC’s neuroprotective effects on behavioral models.

They used a radial arm water maze (RAWM) to test spatial memory.

RAWM tests revealed that treating aged APP/PS1 mice with low doses of THC for three months increased their spatial learning skills in a dose-dependent way (Wang et al., 2022).

Based on the evidence, we hypothesize that IGC-AD1 may have several AD modifying benefits, including:

Reduction in Aβ expression without a reduction in APP.

Reduction in Aβ aggregation and consequently plaques.

Enhanced mitochondrial functioning.

Reduction in the phosphorylation of tau and consequently a reduction in neurofibrillary tangles (NFTs).

Research has shown that micro-dosing of THC could increase the functioning of mitochondria on AD cell lines (Cao et al., 2014) and potentially promote the growth of new pathways (neurogenesis) (Suliman, et al., 2018).

Micro-dosing of THC affects the brain radically differently from the normal dosing in the FDA-approved prescription drug, Dronabinol.

For example, there is a significant body of research showing that THC is neuro-toxic at normal levels, but micro-doses of THC have been shown to be non-toxic to neurons.

With the exciting results of these pre-clinical studies, the Company developed an oral formulation, IGC-AD1, and completed a Phase 1 trial on AD patients.

Alzheimer’s affects not only cognition but also mood and behavior, changes which increase in intensity as the disease progresses.

Approximately 6.5 million individuals in the U.S.

live with Alzheimer’s, and a majority experience a medical syndrome called agitation in Alzheimer’s dementia.

There are various symptoms associated with this medical syndrome or condition, such as screaming, pacing, biting, disrobing, excessive motor movements, physical aggression, and verbal aggression, among others.

This medical condition makes it very difficult for caregivers to manage their loved ones and is associated with increased hospitalization and accelerated cognitive decline.

Agitation is a behavioral syndrome characterized by increased, often undirected, motor activity, restlessness, aggressiveness, and emotional distress.

About 76% of AD patients suffer from agitation (Van der Mussele, et al., 2015).

While there can be no guarantee, we expect the Phase 2 trial to take between 12 and 18 months to complete, barring a variety of unknown factors, such as a resurgence of COVID and the enforcement of lockdowns and travel restrictions.

Symptoms of AD depend on the stage of the disease:

preclinical, mild, moderate, or severe.

NPS like agitation, apathy, delusions, hallucinations, and sleep impairment are common accompaniments of dementia.

Loss of functionality, including progressive difficulty in performing instrumental and basic activities of daily living, is also seen with disease progression (Tang et al., 2019).

There is a spectrum of behavioral disorders that can affect patients with AD.

These include agitation, anxiety, disturbance of the sleep cycle, depression, inappropriate sexual behavior, disinhibition, and irritability, among others (Lyketsos, et al., 2011).

These behavioral disturbances not only affect the patient’s quality of life but also cause extreme emotional distress for the caregivers.

These disturbances can become very difficult to manage, so most of the time, combinational therapy is used (Matsunaga, et al., 2015).

This can cause secondary undesirable effects, such as excessive sleepiness, which diminishes the capability of the patient to be active and alert during the day;

dizziness, which can increase the risk for falls (Allan, et al., 2005);

worsening of cognitive function, which in turn worsens functionality (Paterniti S, et al., 2002);

and even death due to cardiovascular complications (Qiu, et.

Background on Agitation in Alzheimer ’ s dementia

We are currently developing IGC-AD1 for the treatment of agitation in Alzheimer’s dementia (“AAD”).

There is only one FDA-approved pharmacological treatment for the indication of AAD.

The National Institute on Aging (“NIA”) at the National Institutes of Health (“NIH”) defines Alzheimer’s disease (“AD”) as an irreversible, progressive brain disorder that destroys memory and thinking skills.

AD is a progressive neurodegenerative disorder that manifests initially as forgetfulness, advancing to severe cognitive impairment and memory loss.

It is a common form of dementia and afflicts more than 6.5 million individuals in the United States, a number that is anticipated to increase to approximately 14 million by 2050.

In addition to cognitive decline, individuals diagnosed with AD typically experience behavioral and psychological symptoms, including agitation and aggression.

These symptoms are seen in a high percentage of AD sufferers, with agitation being reported in over 70% of patients.

Agitation is characterized by emotional distress, aggressive behaviors, disruptive irritability, and disinhibition.

Agitation in Alzheimer’s dementia has been associated with increased caregiver burden, decreased functioning, earlier nursing home placement, and death.